The present invention relates to a method for preparing crystalline cefadroxil hemihydrate.
Cefadroxil is chemically 7-[D-xcex1-amino-xcex1-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. It is a well-known antibiotic substance having antibacterial activity and is disclosed in U.S. Pat. No. 3,489,752. U.S. Pat. No. 3,985,741 discloses preparation of cefadroxil by acylation of 7-aminodesacetoxycephalosporanic acid with the mixed anhydride of D-(xe2x88x92)-xcex1-(p-hydroxyphenyl)glycine when the latter""s xcex1-amino group has been blocked with a xcex2-keto compound such as methyl acetoacetate.
U.S. Pat. No. 4,504,657 claims a different form of cefadroxil that is the crystalline form of cefadroxil, known as cefadroxil monohydrate having a well-defined X-ray diffraction pattern. This crystalline cefadroxil monohydrate is obtained by acylation of silylated 7-aminodesacetoxycephalosporanic acid with D(xe2x88x92)xcex1-amino-xcex1-(p-hydroxyphenyl)acetyl chloride hydrochloride.
U.S. Pat. No. 4,962,195 discloses yet another novel crystalline cefadroxil having a water content of about 3% and characterized by distinct X-ray diffraction properties. This novel cefadroxil is called xe2x80x9ccefadroxil hemihydratexe2x80x9d and is shown to be more stable than crystalline cefadroxil monohydrate.
U.S. Pat. Nos. 4,962,195 and 5,023,331 disclose a method of producing cefadroxil hemihydrate by adding to an aqueous solution containing cefadroxil prepared from 7-aminodesacetoxycephalosporanic acid, a solvent selected from the group consisting of dimethylacetamide, monomethylformamide or N-methyl-2-pyrrolidone at a controlled pH (5.5 to 6.0) to give the corresponding cefadroxil solvate which precipitates and is filtered off. After the cefadroxil solvate is dried, it is slurried with a mixture of methanol-isopropyl alcohol 30:70 to 50:50 by volume at a temperature in the range of 45xc2x0 C. to 55xc2x0 C., to give crystalline cefadroxil hemihydrate which is isolated by filtration.
Both of these patents report that the use of the cefadroxil solvates of dimethylacetamide, of N-methyl-2-pyrrolidone and of monomethylformamide is critical for the preparation of crystalline cefadroxil hemihydrate and that it was impossible to obtain the desired crystalline cefadroxil hemihydrate from the known cefadroxil dimethyl formamide solvate (U.S. Pat. Nos. 3,985,741, 4,504,657 and U.S. Pat. No. Re. 31,730). It always resulted in the isolation of the known crystalline cefadroxil monohydrate due to the fact that the cefadroxil dimethyl formamide solvate has a K.F. value of 1.8% or more.
The use of cefadroxil solvates as disclosed in U.S. Pat. Nos. 4,962,195 and 5,023,331 pose serious problems of filterability at a commercial manufacturing scale and the solvents used are quite expensive. These disadvantages make the process operationally tedious and inefficient cost-wise.
It is an object of the present invention to solve the problems associated with the prior art. According to one aspect, the present invention provides an efficient method for the preparation of cefadroxil hemihydrate from cefadroxil dimethyl formamide solvate. The process provides obvious benefits with respect to economics and convenience to operate at a large scale.
The present invention specifically describes a method for producing crystalline cefadroxil hemihydrate of Formula II, from cefadroxil dimethyl formamide solvate which comprises slurrying cefadroxil dimethyl formamide solvate of Formula I, with a mixture of a lower alkanol and water, at a temperature in the range of about 40xc2x0 C. to 50xc2x0 C., and isolating the crystalline cefadroxil hemihydrate from the reaction mixture.
Lower alkanol is selected from methanol, n-propanol, isopropanol and mixtures thereof. Cefadroxil dimethyl formamide solvate is dried to preferably achieve a water content less than 1.8%. Crystalline cefadroxil hemihydrate can be isolated by any means such as filtration, decantation, centrifugation or filtration under vacuum. Crystalline cefadroxil hemihydrate is preferably isolated by filtration.
U.S. Pat. No. 4,962,195 and 5,023,331 report that the use of the mixture methanol/isopropyl alcohol has proved to be essential to give the desired cefadroxil hemihydrate and if ethyl alcohol is used, the cefadroxil molecule is decomposed. The use of methanol alone gives an exceedingly high amount of residual methanol (more than 0.4%).
It has been surprisingly found when mixture of methanol and water is used, cefadroxil hemihydrate with a methanol content less than 0.2% is obtained, as opposed to the use of methanol above. Use of a single solvent over a mixture of solvents gives the obvious benefits with respect to the recovery of solvent and thus is more economical.
According to another aspect of the invention, a single solvent is used in the preparation of cefadroxil hemihydrate from cefadroxil dimethyl formamide solvate.
Cefadroxil dimethyl formamide solvate of Formula I: 
is prepared by the methods known in the art, specifically example 2A of U.S. Pat. No. 4,504,657.